Spinal Cord Gray and White Matter Damage in Different Hereditary Spastic Paraplegia Subtypes

Servelhere, Katiane Raisa; Casseb, Raphael Fernandes; Lima, Fabrício Diniz de; Rezende, Tiago Marques de; Ramalho, Luciana; França, Marcondes C.

doi:10.3174/ajnr.a7017

Cited by 10 publications

(10 citation statements)

References 27 publications

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“…29 While each subtype of HSP has its distinct genetic cause and pathophysiology, length-dependent axonal degeneration has been consistently found in pathologic studies, 30 and imaging studies have reported spinal cord atrophy and corticospinal tract abnormalities in a variety of HSP subtypes. [31][32][33] We therefore believe axonal degeneration and the subsequent release of NfL to be a common downstream process caused by possibly distinct upstream pathways. Nevertheless, differences in the rate of axonal decay and the involvement of additional neuroanatomical structures may lead to different sNfL levels across the subtypes of HSP.…”

Section: Discussionmentioning

confidence: 99%

“…When comparing our findings to results obtained by other methods, imaging studies of the spinal cord and the corticospinal tract seem most suited, as they provide crosssectional data on the course of SPG4. Several magnetic resonance imaging studies in patients with SPG4 have found atrophy of the spinal cord 31,32 or abnormalities of the corticospinal tract. 33,[35][36][37] Some of these studies have reported a correlation of disease duration and severity with the extent of corticospinal tract abnormalities on the other side.…”

Section: Discussionmentioning

confidence: 99%

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Characteristics of serum neurofilament light chain as a biomarker in hereditary spastic paraplegia type 4

Keßler

Serna-Higuita

Wilke

et al. 2022

Ann Clin Transl Neurol

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Objective: While the anticipated rise of disease-modifying therapies calls for reliable trial outcome parameters, fluid biomarkers are lacking in spastic paraplegia type 4 (SPG4), the most prevalent form of hereditary spastic paraplegia. We therefore investigated serum neurofilament light chain (sNfL) as a potential therapy response, diagnostic, monitoring, and prognostic biomarker in SPG4. Methods: We assessed sNfL levels in 93 patients with SPG4 and 60 healthy controls. The longitudinal study of sNfL levels in SPG4 patients covered a baseline, 1-year follow-up and 2-year follow-up visit. Results: Levels of sNfL were significantly increased in patients with genetically confirmed SPG4 compared to healthy controls matched in age and sex (p = 0.013, r = 0.2). Our crosssectional analysis revealed a greater difference in sNfL levels between patients and controls in younger ages with decreasing fold change of patient sNfL elevation at older ages. Over our observational period of 2 years, sNfL levels remained stable in SPG4 patients. Disease severity and progression did not correlate with sNfL levels. Interpretation: Our longitudinal data indicate a stable turnover of sNfL in manifest SPG4; therefore, sNfL levels are not suitable to monitor disease progression in SPG4. However, sNfL may be valuable as a therapy response biomarker, since its turnover could be modified by interventions. As the course of sNfL levels appears to be most dynamic around the onset of SPG4, the ability to detect a therapy response appears to be especially promising in younger patients, matching the need to initiate treatment in early disease stages.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Characteristics of serum neurofilament light chain as a biomarker in hereditary spastic paraplegia type 4

Keßler

Serna-Higuita

Wilke

et al. 2022

Ann Clin Transl Neurol

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show abstract

Section: Discussionmentioning

confidence: 99%

“…Spinal cord atrophy has been described in a few studies of SPG5 patients or other HSP subtypes [ 11 – 13 ]. However, only a small selection of spinal cross-sectional area or diameter were measured [ 11 – 13 ]. To our knowledge, our study is the first one to thoroughly investigate the whole length of cervical and thoracic regions, with measurements of both cross-sectional area and antero-posterior/ transverse diameter.…”

Section: Discussionmentioning

confidence: 99%

Potential markers for sample size estimations in hereditary spastic paraplegia type 5

Lin

Liu

et al. 2021

Orphanet J Rare Dis

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Background Aim to identify potential biomarkers to assess therapeutic efficacy for hereditary spastic paraplegias type 5 (SPG5) by investigating the clinical, cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) features. Methods We performed a cross-sectional study to compare SPG5 patients with age- and sex-matched healthy controls who underwent conventional and quantitative MRI techniques of spinal cord (C1-T9) and brain. SPG5 patients also underwent assessment for clinical status and CSF biomarkers (27-hydroxycholesterol, neurofilament light). We identified a set of markers with standardized effect sizes (|t|> 0.5) to estimate sample sizes for disease progression (disease duration > 14 years vs. ≤ 14 years). Results Seventeen genetically confirmed SPG5 patients (11 men, 6 women; age range, 13–49 years; median disease duration, 14 years) were enrolled. Compared to healthy controls, the total spinal cord area (SCA) of SPG5 patients was reduced particularly at the thoracic levels (cervical levels: 12–27%; thoracic levels 41–60%). Patients did not show significant alterations of brain signal abnormalities or atrophy relative to controls. A total of 10 surrogate markers were selected and a minimum sample size was achieved with the measurement of SCA on T9 (n = 22) much less that what would be required if using clinical disability assessment (n = 124). Conclusions SPG5 patients showed distinct MRI features of spinal cord atrophy without significant brain alterations. Our finding supports the measurements of spinal cord on T9 level as potential endpoint for SPG5 clinical trials. Trial registration ClinicalTrials.gov, NCT04006418. Registered 05 July 2019, https://clinicaltrials.gov/ct2/show/NCT04006418?term=NCT04006418&draw=2&rank=1.

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“…This combined approach proved useful to uncover SC changes and to identify potential biomarkers in several other neurodegenerative conditions, such as Friedreich's ataxia, amyotrophic lateral sclerosis, and hereditary spastic paraplegia. [10][11][12] In the current study, our aim was to determine in vivo the pattern and extent of SC damage in RFC1-related disorder. Simultaneously, we investigated the potential clinical correlates of these neuroimaging abnormalities.…”

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confidence: 99%

RFC1‐Related Disorder: In Vivo Evaluation of Spinal Cord Damage

et al. 2022

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A BS TRACT: Background: RFC1-related disorder is a novel heredodegenerative condition with a broad phenotypic spectrum. Its neuropathological bases are not yet fully understood, particularly regarding the pattern, extent, and clinical relevance of spinal cord (SC) damage. Objectives: The objectives were to determine the SC structural signature in RFC1-related disorder in vivo and to identify potential clinical correlates for these imaging abnormalities. Methods: We enrolled 17 subjects with biallelic RFC1 (AAGGG)n expansions and 11 age-and sex-matched healthy controls that underwent multimodal magnetic resonance imaging SC acquisitions in a 3T Philips Achieva scanner. Both global morphometry and tractspecific analyses were then performed across all cervical levels. Between-group comparisons were assessed using nonparametric tests.Results: In the patient group, mean age and disease duration were 62.9 AE 9.3 and 9.3 AE 4.0, respectively. Compared to controls, patients had remarkable SC cross-sectional area reduction along all cervical levels but anteroposterior flattening only in the lower cervical levels. There was also prominent SC gray matter atrophy. Diffusivity abnormalities were identified in the dorsal columns but not in the lateral corticospinal tracts. Disease severity did not correlate with these imaging parameters. Conclusion: SC damage is a hallmark of RFC1-related disorder and characterized by gray as well as white matter involvement. In particular, dorsal columns are severely and diffusely affected. The clinical correlates of these imaging abnormalities still deserve additional investigations.

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Spinal Cord Gray and White Matter Damage in Different Hereditary Spastic Paraplegia Subtypes

Cited by 10 publications

References 27 publications

Characteristics of serum neurofilament light chain as a biomarker in hereditary spastic paraplegia type 4

Characteristics of serum neurofilament light chain as a biomarker in hereditary spastic paraplegia type 4

Potential markers for sample size estimations in hereditary spastic paraplegia type 5

RFC1‐Related Disorder: In Vivo Evaluation of Spinal Cord Damage

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